This project is designed to discover important regulatory molecules that control T cell development within the thymus and peripheral immune responses. It is known that blood precursor cells appear in the embryonic region that will become the thymus at day 10/11 of embryogenesis in the mouse. These cells go through a series of developmental stages during which they acquire various capacities that will be eventually needed by the mature T cell to carry out appropriate immune functions. We and others have shown that signals from the cells that form the stromal shell of the thymus provide signals to cause the precursor cells to become T cells and not other types of lymphocytes such as B or natural killer (NK) cells. We have found that the earliest thymic precursors can be subdivided by a cell surface protein called NK1.1 that allows us to identify cells that have committed themselves to becoming T cells. We have also identified the p53 molecule as a checkpoint in thymic development once the precursor cells have committed to becoming T cells. Finally, we have succeeded in pursuing gene knock-outs in mice for the signalling molecules Ly-GDI and RLK which are highly expressed within developing thymocytes. Interestingly, homozygous deficiencies of these genes did not detectably alter thymocyte development but rather caused functional abnormalities in mature T cells. In particular, our data show that the RLK gene is a tyrosine kinase that plays a role in helping T cells to fight infections. These results may have important implications for bone marrow transplantation and immunodeficiency diseases involving T cells.
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